甲状旁腺结构基础与荷尔蒙相关的蛋白质绑定conformation-selective肽的甲状旁腺激素受体和设计。
文章的细节
-
引用
复制到剪贴板 -
Pioszak AA,帕克NR, Gardella TJ,他许
甲状旁腺结构基础与荷尔蒙相关的蛋白质绑定conformation-selective肽的甲状旁腺激素受体和设计。
J生物化学杂志。2009年10月9日,284 (41):28382 - 91。doi: 10.1074 / jbc.M109.022905。Epub 2009年8月12日。
- PubMed ID
-
19674967 (在PubMed]
- 文摘
-
甲状旁腺素和PTH-related蛋白质(PTHrP)是两个相关的肽,控制钙/磷体内平衡和骨骼发展,分别通过激活的甲状旁腺素/ PTHrP受体(PTH1R), B类G protein-coupled受体。两个肽吸引临床能力刺激骨形成。甲状旁腺素和PTHrP显示不同的两种截然不同的选择性PTH1R构象,但如何绑定到受体不同尚不清楚。高分辨率晶体PTHrP绑定到细胞外结构域(ECD) PTH1R表明PTHrP结合作为相同的疏水两性α螺旋槽在儿童早期开发的甲状旁腺素,但相比之下直,连续的甲状旁腺素螺旋,PTHrP螺旋轻轻弯曲,c端“解除”。The receptor accommodates the altered binding modes by shifting the side chain conformations of two residues within the binding groove: Leu-41 and Ile-115, the former acting as a rotamer toggle switch to accommodate PTH/PTHrP sequence divergence, and the latter adapting to the PTHrP curvature. Binding studies performed with PTH/PTHrP hybrid ligands having reciprocal exchanges of residues involved in different contacts confirmed functional consequences for the altered interactions and enabled the design of altered PTH and PTHrP peptides that adopt the ECD-binding mode of the opposite peptide. Hybrid peptides that bound the ECD poorly were selective for the G protein-coupled PTH1R conformation. These results establish a molecular model for better understanding of how two biologically distinct ligands can act through a single receptor and provide a template for designing better PTH/PTHrP therapeutics.